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Heart Valve Disease

Heart valve disease.

A heart valve is a structure at the exit of a heart chamber, consisting of two or three cup shaped flaps, that allows blood to flow out of the chamber but prevents it from washing back. There are four heart valves: aortic, pulmonary, mitral, and tricuspid. The opening and closing of the heart valves during each heart cycle produces heart sounds which can be heard with a stethoscope.

Disorders of heart valves

Heart valves may be affected by stenosis (narrowing), in which the heart must work harder to force blood through, or by incompetence or insufficiency (leakiness), which makes the valve unable to prevent regurgitation (backwash) of blood. These defects cause heart murmurs.

Defects of the heart valves may be present from birth or acquired later in life. The most common congenital valve defects are aortic stenosis and pulmonary stenosis. Acquired heart-valve disease is usually the result of degenerative changes or ischaemia (reduced blood supply) affecting part of the heart and leading to aortic stenosis or mitral incompetence. Rheumatic fever can cause mitral stenosis, mitral incompetence, defects of the aortic valve, tricuspid stenosis, and tricuspid incompetence. Heart valves may also be damaged by bacterial endocarditis.

Heart-valve disorders commonly lead to heart failure, arrhythmias, or symptoms that arise from reduced blood supply to the tissues.

Heart-valve defects may be diagnosed by auscultation, chest X-ray, ECG, or echocardiography and may be corrected by heart-valve surgery.

Heart-valve surgery

This is an operation to correct a heart valve defect or to remove a diseased or damaged valve. A heart valve may have to be repaired, widened, or replaced because it is either incompetent (leaky), stenotic (narrowed), or both. Widening of a valve may involve valvotomy or valvuloplasty. A damaged valve can be replaced by a mechanical one (fashioned from metal and plastic), a valve constructed from human tissue, a pig valve, or a valve taken from a human donor after death. A heart–lung machine is used during valve replacement.

After heart-valve surgery, there may be symptoms of breathlessness for several weeks that require continued medication. Some people require long-term treatment with anticoagulant drugs to prevent the formation of blood clots around the new valve. Certain types of replacement valve, such as mechanical valves, are more likely to cause clots than other types.

Heart valve disease in detail -technical

Topics covered:

Essentials

Introduction

The mitral valve

Aortic valve disease

Right heart valve disease

Further reading

Essentials

Rheumatic valve disease remains prevalent in developing countries, but over the last 50 years there has been a decline in the incidence of rheumatic valve disease and an increase in the prevalence of degenerative valve pathology in northern Europe and North America. In all forms of valve disease, the most appropriate initial diagnostic investigation is almost always the echocardiogram.

Management—the only medical treatments in mitral stenosis are (1) prophylactic measures against rheumatic fever and endocarditis; (2) anticoagulation to prevent systemic embolism; and (3) diuretics for raised left atrial pressure. Patients who are symptomatic need intervention by either surgical valvotomy or catheter–balloon valvuloplasty, whether or not they have pulmonary hypertension. Early intervention—before the development of atrial fibrillation and an enlarged left atrium—is recommended, provided a conservative operation is possible. Mitral valve replacement is reserved for cases where the mitral valve cannot be repaired.

Mitral regurgitation is an isolated volume overload on the left ventricle, providing the physiological equivalent of afterload reduction so that a normal forward cardiac output is maintained by the combination of increased ejection fraction and higher preload. Patients with mild regurgitation may not have any symptoms: those with severe regurgitation are likely to present with dyspnoea. Characteristic physical signs are an apex beat that may be prominent and displaced, an apical pansystolic murmur, and a third heart sound. The loudness of the murmur generally correlates with severity of regurgitation. The cardinal signs of mitral prolapse are a mid-systolic click followed by a murmur.

Endocarditis prophylaxis may be recommended to high risk patients with regurgitation. Patients in atrial fibrillation should be given anticoagulants. The development of symptoms suggests the need for surgical correction to avoid development of irreversible left ventricular dysfunction. Assessment during routine follow-up should identify those likely to need surgical intervention even in the absence of symptoms, with an effective regurgitant orifice of over 40 mm2 being one proposed indication. It is generally considered that a left ventricular end-systolic dimension more than 50 mm indicates a poor prognosis and that surgical intervention is unlikely to be of benefit. If technically possible, mitral valve repair results in a much better clinical outcome than does valve replacement, but mitral replacement by a mechanical valve or bioprosthesis is the only option for irreparable valves.

Aortic stenosis

Aortic stenosis may be at subvalvar, valvar, or supravalvar level, the commonest being valvar stenosis. Age-related degenerative calcific disease is the commonest cause in western Europe and the United States of America. Other causes include congenital bicuspid aortic valve and rheumatic disease (always associated with aortic regurgitation, ‘mixed aortic valve disease’, and usually with rheumatic mitral disease).

With the increase in outflow-tract resistance in aortic stenosis, left ventricular wall stress increases and hypertrophy develops, preserving overall ventricular systolic function, but potentially at the expense of subendocardial ischaemia. Patients with mild disease may be asymptomatic, and even severe stenosis may be silent, but breathlessness, angina, and syncope are typical. Characteristic physical signs are a slowly rising, low-amplitude pulse, a narrow pulse pressure, a sustained apex beat, and a long and harsh ejection systolic murmur that is loudest at the base (second right intercostal space, also known as the aortic area) of the heart, and in most cases radiates to the carotids (where a thrill may be palpable).

Management—patients with moderate or severe disease should be advised to avoid strenuous exercise. Prophylaxis against endocarditis may be recommended to high risk patients. Asymptomatic patients with mild or moderate aortic stenosis require follow-up; those with severe disease (pressure gradient 70 mmHg) need aortic valve replacement.

The left ventricular stroke volume is significantly increased, which is accommodated by an increase in left ventricular cavity size. As disease progresses, end-systolic volume increases out of proportion to stroke volume, and eventually these changes lead to irreversible damage. The onset of symptoms, particularly breathlessness, coincides with the onset of left ventricular disease. Characteristic physical signs of chronic severe aortic regurgitation are a large amplitude ‘collapsing’ pulse (which when severe can induce pulsations in many parts of the body), a low diastolic blood pressure (<50 mmHg) and/or a high pulse pressure (>80 mmHg), an apex beat that is sustained and/or displaced, and an early diastolic, decrescendo murmur, loudest at the left sternal border. Acute aortic regurgitation causes the patient to be cold and shut down, with tachycardia, hypotension, and a short early diastolic murmur that is easily missed.

Management—medical treatment of chronic aortic regurgitation includes angiotensin converting enzyme (ACE) inhibitors and/or calcium channel blockers to reduce afterload. Patients with a dilated aortic root should be given β-blockade with ACE inhibition/angiotensin receptor blockers. Prophylaxis against endocarditis may be recommended to high risk patients. Although patients with severe chronic aortic regurgitation may remain asymptomatic, valve replacement should be offered when there is progressive increase in left ventricular end systolic dimension, which should not be allowed to reach more than 40 mm.

Tricuspid stenosis—this is rare, but most often caused by rheumatic disease that almost invariably simultaneously affects the mitral valve. Symptoms include fatigue, dyspnoea, and fluid retention. On auscultation at the left or right sternal edge, a mid-diastolic murmur is heard and a tricuspid opening snap may be present. Diuretics can help to minimize fluid retention. Severe tricuspid stenosis needs surgical repair, or replacement if additional regurgitation is present.

Tricuspid regurgitation —significant disease is most commonly secondary to pulmonary hypertension and/or right heart dilatation; the commonest noncongenital primary cause is infective endocarditis. Symptoms include fluid retention and hepatic congestion. A raised venous pressure with prominent V-wave is expected. Other signs include a pansystolic murmur at the left or right sternal edge (in one-third of cases), expansile pulsation of the liver (in most), and peripheral oedema/ascites. Diuretics and ACE inhibitors may reduce systemic venous pressure and right ventricular size, even restoring valve competence in some cases. Valve repair or replacement may be advised in some cases.

Pulmonary stenosis—a rare condition usually caused by rheumatic disease or carcinoid syndrome. Fatigue and dyspnoea are the main symptoms. Characteristic physical signs are a prominent venous ‘a’ wave in the neck and an ejection systolic murmur loudest at the upper left sternal edge. Balloon valvuloplasty is the procedure of choice if intervention is warranted.

Pulmonary regurgitation—significant disease is rare, but usually caused by rheumatic disease, carcinoid, and endocarditis. The characteristic physical sign is a soft early diastolic murmur in the left upper parasternal region. Arrhythmia or progressive right ventricular dilatation are indications for surgery, using homograft or conduit and valve.

Introduction

Over the last 50 years there has been a significant shift in the causes of heart valve disease in Northern Europe and North America, with a decline in the incidence of rheumatic valve disease and an increase in the prevalence of degenerative valve pathology. Rheumatic valve disease remains prevalent in the developing countries, particularly in areas with limited clinical services. The commonest valve involved with rheumatic pathology is the mitral valve, but the aortic and tricuspid valves can also be involved. The apparent increase in the diagnosis of valve disease could be due either to ageing of the population or to the extensive use of echocardiography in cardiology clinics. Age affects the valves, making leaflets thicker with fibrous strands and adipose tissue deposition at the closure lines of the leaflets. Isolated myxomatous changes may also occur in the valve fibrosa. In patients with a suspected diagnosis of endocarditis these changes can add to diagnostic difficulty since they may look like small vegetations, and they also need to be distinguished from papillary muscle fibroelastoma.

Medical treatment of valve disease is limited, focusing mostly on prophylaxis against endocarditis and ventricular dysfunction as well as optimizing haemodynamics. Although surgical repair is the main conventional treatment of severe valve disease, the need for this is 5 to 10 times less than that for coronary artery disease.

Valve-related mortality is more common in aortic valve disease than mitral valve disease, largely due to the frequent development of left ventricular dysfunction that causes congestive heart failure. Other causes of death in valve disease are additional pathologies such as coronary artery disease, endocarditis, or arrhythmia.

The mitral valve

Normal mitral valve anatomy and function

Optimum function of the mitral valve depends on the intact function of all its components—leaflets, chordae, annulus, and papillary muscles, in addition to the left atrium and the left ventricle. A normal mitral valve does not close passively. In addition to the pressure difference between the ventricle and atrium in systole, the annular contraction and papillary muscle contraction play an important role in the competence of the mitral valve. The anterior mitral valve leaflet represents a continuation of the posterior aortic root wall. The annular fibrous ring is located mainly posteriorly; it is usually D- shaped but there is significant variability in different individuals. The normal diameter of the mitral annulus is around 3 cm with a circumference of 8 to 9 cm: it is not a passive structure, so in addition to its normal movement towards the apex in systole, the contraction of the posterior myocardial muscle shortens its diameter by 25%, with such movement being a very important component in the mechanism of mitral valve competence.

Change in the size and shape of the left atrial cavity is a cause for incompetence of the mitral valve by enlarging the annular diameter. Loss of atrial mechanical function may contribute significantly to the development of mitral regurgitation in patients with atrial fibrillation. Likewise, atrial fibrillation itself has been shown to contribute to the enlargement of the left atrium and consequently the development of mitral regurgitation.

The two leaflets of the mitral valve meet at the medial and lateral commissures. The area of the U-shaped anterior leaflet is larger than that of the posterior leaflet, which is wider and shorter than the anterior leaflet. The posterior leaflet is made up of a number of scallops, commonly three. The two leaflets coapt at the zone of apposition, leaving an overlapping segment 5 mm long.

The chordal anatomy of the mitral valve is complicated, with around 12 primary chordae rising from each papillary muscle. These divide into secondaries and numerous tertiary branches that attach themselves to the margins of the two leaflets. In addition, a number of basal chordae also attach themselves to the ventricular surface of the leaflets and to the commissures. The location of the chordae follows that of the papillary muscles anterolaterally and posteromedially. Any rupture or redundancy of the chordae or extra tissue in the leaflets results in mitral regurgitation.

Mitral stenosis

Causes

The most common cause of mitral stenosis, which affects women more than men (2:1), is rheumatic valve disease. The rheumatic process involves not only the leaflets but may also affect the chordae and the annulus, causing fibrosis and superimposed calcification. The rheumatic leaflets become thickened and fibrosed, and the commissures fuse. The end result of this pathology is a reduction in mitral valve area, the rigid movement of the leaflets and the commissural fusion together contributing to the limited flow across the mitral valve orifice and hence stenosis. It is not uncommon for the fibrotic process to involve the subvalvar region in an aggressive way, thus causing flow to be limited at the level of the subvalvar apparatus. In such cases the chordae become short and the inflow tract of the left ventricle become tunnel-like.

Mitral annular calcification is another cause of raised filling velocities: this is seen in older people with the calcification limited to the annulus and the proximal segments of the leaflets, but the leaflets themselves are normal. A very uncommon cause of mitral stenosis is congenital mitral stenosis, which may be associated with other cardiac abnormalities. Infective endocarditis with bulky vegetations may rarely cause restriction of mitral flow, and patients with systemic lupus erythematosus (SLE) can develop fibrosis of the mitral cusps with commissural fusion following Liebman–Sachs endocarditis.

Pathophysiology and complications

The important consequence of mitral stenosis is its effect on left atrial pressure and size and on the pulmonary vasculature. As the valve area falls progressively, left atrial pressure rises, its size increases, and the pulmonary venous pressure also increases. In most patients with rheumatic mitral valve disease the left ventricle is normal in size and systolic function unless the valve stenosis is severe and making the ventricle under filled.

With a mild degree of mitral stenosis, reduced orifice area is compensated by increased flow during atrial systole. As the valve stenosis becomes more severe, the left atrial pressure increases, the pressure difference between the atrium and the ventricle increases, and the filling occurs throughout diastole. In severe mitral stenosis the pressure difference may be as high as 25 to 30 mmHg. Long-standing disease may result in irreversible pulmonary hypertension secondary to the raised left atrial pressure. Atrial fibrillation also develops, with loss of mechanical atrial function.

A normal mitral valve area is of the order of 5 cm2, compared to a valve area in a patient with severe mitral stenosis of less than 1 cm2. Effective mitral valve area changes very little with increase in heart rate compared to aortic valve area (which increases), the reason probably being the smaller number of commissures that assist opening of the mitral valve compared to the aortic valve. During exercise, particularly in atrial fibrillation, diastolic time falls and the fixed valve area causes raised left atrial pressure and pulmonary venous pressure.

Left atrial dilatation

Progressive reduction in mitral valve orifice area causes progressive increase in left atrial pressure and size and pulmonary venous pressure. Left atrial dilatation is associated with reduction in its mechanical function that slows down intra-atrial blood circulation (swirling). With progressive disease and development of atrial fibrillation, the circulation in the atrium becomes very sluggish and echocardiography may demonstrate spontaneous echo-contrast, particularly on transoesophageal images. Such patients are given anticoagulants in order to avoid clot formation and hence the risk of transient ischaemic attacks (TIA). Almost one-fifth of the patients undergoing surgery for mitral stenosis have left atrial thrombus, and in one-third of them the thrombus is restricted to the atrial appendage.

Atrial fibrillation

This is the most common complication of mitral stenosis and its prevalence increases with age, being found in 70% of patients in their thirties and in 80% of those in their fifties. The presence of pulmonary hypertension raises the prevalence of atrial fibrillation. The Framingham study estimated a 20-fold increase in risk of stroke in patients with atrial fibrillation and mitral stenosis compared to only 5-fold increase in those without mitral valve disease. Left atrial thrombus may also form in patients with a dilated left atrium with spontaneous echo-contrast who are in sinus rhythm. The loss of left atrial appendage mechanical function has been proposed as a possible mechanism behind blood stagnation and thrombus formation.

Left ventricular dysfunction

Although in most cases of mitral stenosis the left ventricle is normal in size and systolic function, in some diastolic function may be impaired and end-diastolic pressure raised. This could be related to additional pathology, e.g. systemic hypertension and diabetes. The left ventricle is dilated only in the presence of additional coronary artery disease. Primary rheumatic myocardial disease was proposed years ago, but no convincing evidence has ever come to light.

Pulmonary hypertension

With the increase in left atrial pressure, the pulmonary venous pressure increases and hence pulmonary arterial pressure also rises. Although pulmonary artery pressure corresponds to the degree of increase in left atrial pressure, a discrepancy between the two may reflect a raised pulmonary vascular resistance. A normal pressure drop across the pulmonary bed is of the order of 10–15 mmHg. The pulmonary hypertension is not always reversible after valve surgery. For any degree of mitral stenosis patients can display a wide range of pulmonary pressures, but it is very rare for secondary pulmonary hypertension to develop with left atrial pressure <20 mmHg in the setting of isolated mitral stenosis.

Right heart disease

With the development of pulmonary hypertension the right ventricle becomes hypertrophied and its cavity dilates. This is also reflected in right atrial size. Patients with rheumatic mitral valve disease may have additional tricuspid valve involvement in particular, the annulus dilating and causing significant tricuspid regurgitation. Patients with severe tricuspid regurgitation may complain of fluid retention that needs careful management in order to maintain the left-sided cardiac output and obtain tissue perfusion. Long-standing significant tricuspid regurgitation and raised right atrial pressure may cause further deterioration of right ventricular function and congestive heart failure. By that stage the damage is usually irreversible despite any successful mitral valve surgery.

Clinical presentation

Symptoms

Patients may remain asymptomatic with mild mitral stenosis. As the disease progresses, early symptoms are exertional fatigue and breathlessness. With severe mitral stenosis shortness of breath is accompanied by orthopnoea and paroxysmal nocturnal dyspnoea. With the development of pulmonary hypertension, right ventricular dysfunction and tricuspid regurgitation patients may present with fluid retention as well as recurrent chest infection. Atrial fibrillation may be an early symptom in patients with mitral stenosis, particularly palpitations on exercise. Major systemic embolus can also be a presenting symptom, and the condition may be detected for the first time during pregnancy as patients complain of disproportionate dyspnoea.

Physical examination

Long-standing mitral stenosis characteristically causes weight loss and a malar flush. The pulse character is normal, but pulse volume may be reduced and atrial fibrillation is likely. The jugular venous pressure is usually normal unless there is tricuspid regurgitation and/or pulmonary hypertension (see below). The apex is not displaced, but the first heart sound is sometimes palpable (‘tapping apex’), and less frequently the opening snap is also.

The characteristic auscultatory features of rheumatic mitral stenosis are an opening snap in early diastole, a mid-diastolic murmur, and a loud first heart sound. The opening snap is caused by the abrupt tension that develops in the fibrosed leaflets at the termination of the opening movement. It is best heard at the lower left sternal edge or apex, becoming closer to the second heart sound as left atrial pressure rises, and it is absent with leaflet calcification. The diastolic murmur is low pitched and maximal at the apex. It is caused by increased blood flow velocity between the left atrium and left ventricle and is accentuated in late diastole by atrial contraction in patients in sinus rhythm. The longer the mid-diastolic murmur, the more likely that the mitral stenosis is severe. The loud first heart sound is associated with fibrosis of the anterior leaflet and is lost with leaflet calcification. Many patients with mitral stenosis have some degree of mitral regurgitation, which is not significant in the presence of severe stenosis.

In the presence of pulmonary hypertension the jugular venous pressure is raised, there may be a palpable right ventricular heave, and the second heart sound is usually loud. In patients with significant tricuspid regurgitation, whether secondary to pulmonary hypertension or due to rheumatic tricuspid valve, there is a clear V-wave and deep Y descent in the jugular venous pulse, and expansile pulsation of the liver. The murmur of tricuspid regurgitation is not usually prominent.

Investigations

Chest radiograph and electrocardiogram

Early in the disease a chest radiograph may show a completely normal cardiac silhouette. Later, as the disease progresses, left atrial enlargement appears and a prominent left atrial appendage contour becomes very evident. Left atrial double-density and elevation of left main bronchus may also be evident. In patients with raised left atrial pressure, pulmonary vascular redistribution manifest as ‘dilated upper lobe veins’ and interstitial pulmonary oedema ‘Kerley B lines’ may be seen. The central pulmonary arteries become prominent as pulmonary hypertension develops, and upper lobe deviation is also seen. Finally, right-sided dilatation may also be seen as tricuspid regurgitation develops.

The electrocardiogram can show a broad and notched P-wave due to left atrial hypertrophy (‘P mitrale’) as a classical finding in mitral stenosis, but will more often reveal atrial fibrillation.

Echocardiography

Echocardiography is the investigation of choice in mitral valve disease. A typical picture of rheumatic valve disease is a short, fibrosed, and stiff posterior leaflet; a fibrosed anterior leaflet that bows down towards the ventricle in diastole; and narrow valve area. Short axis images clearly demonstrate the fused commissures and two-dimensional images show the extent of chordal fibrosis. Planimetry of the mitral valve area in diastole gives an estimate of the degree of stenosis. Continuous wave Doppler assesses the blood flow velocity across the valve. In mild stenosis, transmitral Doppler demonstrates a peak velocity in late diastole compared to in early diastole in severe stenosis. With atrial fibrillation there is a single early diastolic filling component to the left ventricle. A transmitral mean pressure gradient of more than 4 mmHg suggests a moderate degree of stenosis, and a mean pressure gradient of more than 8 mmHg suggests severe stenosis. Colour flow Doppler can provide a quantitative approach for assessing mitral stenosis severity using the proximal isovelocity surface area (PISA) method or the vena contracta method (the vena contracta being the narrowest region of the stenotic jet, just downstream of the valve orifice and reflecting the size of that orifice). Although the latter is easy to use it has its limitations since it varies more with deformation of the mitral orifice area and shape. Colour flow Doppler will also show any mitral regurgitation jet and give some indication of its severity.

Echocardiography also assesses any involvement of the aortic valve or the tricuspid valve by the same or other pathologies. It is now common practice that most patients with mitral valve disease are studied by transoesophageal echo because this provides more detailed assessment of the mitral valve, the subvalvar apparatus, and the presence of left atrial spontaneous contrast and appendage clots.

Cardiac catheterization

Echocardiography has replaced cardiac catheterization in making the diagnosis of mitral stenosis. Catheterization may provide additional information on pulmonary vascular resistance and coronary artery disease before surgery.

Differential diagnosis

The diagnosis of mitral stenosis is usually straightforward on the basis of clinical findings supported by echocardiography, which should distinguish the presence of an Austin–Flint murmur caused by aortic regurgitation (see below) and the rare conditions of left atrial myxoma (see: Tumours of the heart) and cor triatriatum (see: Congenital heart disease in the adult).

Management

There is a significant time lag between the acute event of rheumatic fever and the presentation of mitral stenosis with mild symptoms, which could be up to 15 years. Patients may need another 10 years to develop signs and symptoms of severe stenosis. The likely reason behind this delay is the time needed for rheumatic leaflet fibrosis and calcification to develop and cause raised left atrial pressure. This time lag between acute rheumatic fever and clinical presentation varies significantly between developed and developing countries. In Europe and North America patients need valve surgery for mitral stenosis in their fifties, whereas those in developing countries need it in their thirties. The clinical outcome of patients with unoperated rheumatic mitral stenosis has changed significantly over time, with 20-year follow-up mortality dropping from historically 85% to recently 44% in those who refuse surgery.

Medical

The only medical treatments in mitral stenosis are the prophylactic measures against rheumatic fever (penicillin prophylaxis, see: Acute rheumatic fever) and endocarditis (considered for high risk cases, see: Endocarditis), anticoagulation to prevent systemic embolism, and diuretics for raised left atrial pressure. There is no medication that has a direct effect on slowing disease progress.

Patients with mitral stenosis should be followed up clinically using noninvasive investigations, particularly Doppler echocardiography. The frequency of follow-up should be tailored according to individual patient’s clinical condition and the severity of disease. Whilst this could be every 2 years in a patient with mild stenosis and regurgitation, closer attention is required for the patient with severe stenosis and evidence of pulmonary hypertension. Particularly close follow-up is advised for pregnant women who have mitral stenosis.

In patients who develop atrial fibrillation, attempts to restore sinus rhythm are usually unsuccessful unless associated with surgery. To maintain sinus rhythm the organic mitral lesion should be dealt with either interventionally or surgically. In addition to heart rate control, digoxin may keep a patient with a modestly dilated left atrium in sinus rhythm. However, once atrial fibrillation is established, attention should be diverted to rate control with digoxin, β-blockers, or calcium channel blockers. With persistent atrial fibrillation anticoagulation is essential and INR level should be monitored and maintained at 2.5 to 3.5. Patients recommended for percutaneous mitral valvuloplasty should receive stable anticoagulation therapy for at least3 months before the procedure and transoesophageal echo should exclude left atrial clot. Those who need surgical intervention may receive a maze procedure as a means for restoring the sinus rhythm, which involves surgically creating a single electrical pathway from the sinus node to the atriventricular node, while isolating the abnormal electrical activity of the left and right atrial tissue. Recently, electrophysiological mapping with isolation of pulmonary veins has offered an alternative procedure. The success of the maze procedure varies considerably, ranging between 25% and 80% even after an initially successful procedure. See: Cardiac arrythmias for further discussion.

Patients who are symptomatic need intervention by either surgical valvotomy or catheter balloon valvuloplasty, whether or not they have pulmonary hypertension. Early intervention is highly recommended, before the development of atrial fibrillation and an enlarged left atrium, provided a conservative operation is possible. The percutaneous mitral valvuloplasty procedure involves inserting an Inoue balloon into the mitral valve orifice and inflating it until an increase in mitral valve area is achieved. Contraindications to this procedure are left atrial appendage thrombus, calcified subvalvar apparatus, and/or mitral regurgitation. Early results of this technique are satisfactory, particularly if patients are well selected, e.g. those with relatively mobile, noncalcified leaflets that are not greatly thickened, and without subvavlular thickening. Mitral stenosis may recur following this procedure after the healing period of the split of the fused commissures.

Surgical

Closed mitral valvotomy has been replaced by percutaneous mitral valvuloplasty, but its results are not optimal. There is thus still room for surgical repair of the mitral valve. This is better suited to patients with minimal calcification and those with short chordae. The technique offers the advantage of avoiding replacing the mitral valve, which has effects on left ventricular function. However, in a patient with an irreparable mitral valve the only remaining option is mitral valve replacement.

Closed mitral commissurotomy

This historic procedure aimed at opening the mitral valve by applying a dilator through the ventricular apex, with the surgeon using their finger to feel the valve leaflets and orifice to judge when the desired valve area was achieved. The first successful operations were carried out in 1948. It has been intensively used in the United Kingdom and other countries, with an average mortality of 3 to 4%.

Open mitral valvotomy

This operation requires the use of an extracorporeal circulation and aims at direct visualization of the mitral valve through a medial sternotomy with careful dissection of the fused commissures under direct vision. In contrast to the closed operation, the surgeon is able to deal with the subvalvar apparatus and the fused chordae, and correct chordal shortening if required. The left atrial appendage can also be visualized, and if there is thrombus present it can be removed. With appropriate patient selection and preoperative evaluation open commissurotomy is feasible in most patients, with an operative mortality of approximately 1%.

Mitral valve replacement:

Mitral valve replacement involves either a mechanical or a tissue valve substitute. Surgical mortality varies according to other comorbidities: it is of the order of 3% in patients with isolated mitral valve stenosis but can be as high as 12% in patients with additional pulmonary hypertension. The life of biological mitral valve substitutes, particularly porcine xenografts, is limited to less than 10 years in most adults, hence their use tends to be restricted to very elderly patients. Cryopreserved mitral homografts have been proposed recently as a better option, as has the use of a pulmonary autograft in a Dacron tube, but experience is limited.

Mitral regurgitation

Causes

The most common causes of mitral regurgitation are ischaemic myocardial dysfunction, mitral valve prolapse, and dilated cardiomyopathy. Other causes are given in Table 1.

Table 1 Common causes of mitral regurgitation

Structure primarily affected

Anatomical defect

Cause

Valve cusps

Congenital cleft

Primary atrial septal defect

Isolated

Redundant cusp

Mitral valve prolapse

Marfan’s syndrome

Perforation

Infective endocarditis

Scarring

Rheumatic fever

Ergot-derived dopamine receptor agonists

Chordae

Redundant

Mitral valve prolapse

Marfan’s syndrome

Other connective tissue disease

Rupture

Acute myocardial infarction

Mitral valve prolapse

Marfan’s syndrome

Other connective tissue disease

Infective endocarditis

Rheumatic fever

Shortening

Rheumatic fever

Endomyocardial fibrosis

Papillary muscle

Dysfunction

Ischaemia

Valve annulus

Dilatation

Severe left ventricular disease of any cause—‘dilated cardiomyopathy’

Ischaemic mitral regurgitation

The posteromedial papillary muscle is predisposed to ischaemic dysfunction and infarction because it is supplied by a single branch of the posterior descending artery and tends to have only a few collaterals. The anterolateral papillary muscle receives blood from branches of both the left anterior descending artery and the circumflex artery, so it is less susceptible to ischaemia. Ischaemic disturbances of left ventricular function contribute to the development of mitral regurgitation through a number of mechanisms: (1) regional wall motion abnormalities with adverse ventricular remodelling and systolic tenting of the valve leaflets, (2) left ventricular dilatation and shape change that alters normal alignment of the papillary muscles and results in leaflet tethering and inadequate closure, and (3) annular dilatation leading to inadequate annular contraction. These mechanisms may contribute to further enlargement of the left ventricle and deterioration of its function, which itself would add to the severity of mitral regurgitation. Four clinical presentations are seen in ischaemic mitral regurgitation: acute myocardial infarction, papillary muscle rupture, reversible ischaemic myocardial dysfunction in the presence of preserved left ventricular systolic function, and endstage ischaemic cardiomyopathy with reduced function.

Acute myocardial infarction

Significant mitral regurgitation complicates 3 to 16% of acute myocardial infarctions. Most present within the obvious context of acute myocardial infarction, but some with pulmonary oedema from the acute development of mitral regurgitation. Most patients presenting with myocardial infarction complicated by mitral regurgitation have right and circumflex coronary artery disease that causes inferior wall dysfunction. Mitral regurgitation does not therefore seem to be related to infarct size, but to the extent of ischaemic dysfunction and involvement of the posteromedial papillary muscle. The resulting poor support to the posterior leaflet, referred to as tethering, causes lack of leaflet coaption and valve incompetence. When severe mitral regurgitation develops it carries a poor prognosis, with mortality rising to 25% at 30 days and over 50% at 1 year. The effect of reperfusion on mitral regurgitation remains controversial.

Papillary muscle rupture

Complete papillary muscle rupture causes severe mitral regurgitation and cardiogenic shock that is usually fatal—70% within 24 h without emergency surgery. Surgical repair of the papillary muscle is not feasible in most cases because tissues are necrotic: valve replacement is necessary, with risk influenced by other factors including the severe left ventricular disease that is usually present.

Ischaemic mitral regurgitation in a normal left ventricle

Patients with long-standing ischaemic myocardial dysfunction usually have exertional reversible ischaemia. If this affects the posterior wall of the left ventricle it leads to further deterioration of posterior wall function and consequently the posterior leaflet function with the development of mitral regurgitation. Exertional breathlessness in these patients does not always have to be due to raised end-diastolic pressure and may be caused by a sudden increase in left atrial pressure through the development of mitral regurgitation with exercise, particularly in those with a dilated left atrium. Stress echocardiography is ideal for demonstrating the stress induced ischaemic ventricular dysfunction and the development of mitral regurgitation and raised left atrial pressure, when antianginal therapy and afterload reduction may be beneficial. Patients who develop significant mitral regurgitation with stress and who are accepted for coronary artery bypass surgery should receive mitral valve repair and a ring insertion at the time of surgical revascularisation.

Ischaemic mitral regurgitation in ventricular dysfunction

Mitral regurgitation is very common in patients with longstanding ischaemic left ventricular dysfunction and/or endstage ventricular disease. Since the valve leaflets appear morphologically normal, the mitral regurgitation is described as ‘functional’. However, three-dimensional echocardiographic assessment of the mitral valve proves that it is not entirely normal, with long-standing progressive changes in the interleaflet relations and subvalvar apparatus. Reducing ventricular pressures may improve left ventricular geometry, and lowering blood pressure may reduce mitral regurgitation severity.

Mitral valve prolapse

Mitral valve prolapse is a genetic connective tissue disorder that affects the mitral leaflets, chordae, and annulus, with an autosomal dominant pattern of inheritance and variable penetrance. Histologically the leaflets show thickening of the spongiosa and disruption of the fibrosa with fragmentation. Collagen is also abnormal with high rate of synthesis, deficiency in type III collagen, and splitting of collagen with fibre disarray. The cause has not yet been identified: defects in a collagen gene or in a gene encoding a component of microfibrils, similar to that involved in Marfan’s syndrome, have obviously been considered. The condition is common: 1.5 to 6% of adults have mitral prolapse, depending on definition, and screening of first-degree family members demonstrates prolapse in approximately 30% of cases.

Mitral prolapse can be classified into two types: a benign condition that is seen in young people, commonly women, that does not always progress; and the ‘myxomatous mitral valve disease’ seen in older people, often causing significant mitral regurgitation that needs surgical repair. Overall survival in patients with mitral prolapse is 97% at 6 years and 88% at 8 years, but those with myxomatous mitral valve disease and a flail leaflet have a 10-year survival much less. With posterior leaflet myxomatous prolapse, progressive chronic mitral regurgitation is associated with progressive dilatation of the left atrium and left ventricle.

The commonest site for posterior mitral prolapse is the middle scallop (P2). Significant mitral regurgitation occurs in less than 10% of patients with posterior prolapse compared to 25% of those with anterior leaflet prolapse. In contrast, the incidence of atrial fibrillation and heart failure is significantly higher in posterior leaflet prolapse than in anterior leaflet prolapse. In general severe mitral regurgitation is associated with redundant leaflets, a longer posterior leaflet, and a larger annulus. Chordal distribution may also be abnormal, and there may be a relative scarcity of chordae to the central scallop of the posterior leaflet, increased chordal division or a higher incidence of chordal rupture.

There is a clear relationship between mitral valve prolapse, arrhythmia and sudden death. The annual rate of sudden death in mitral prolapse is approximately 2%, which significantly falls after surgical repair. The risk of endocarditis is estimated at three to eight times that of the general population, the substrate being that leaflet prolapse causes significant turbulence of the blood flow across the valve orifice, disrupting platelet and fibrin deposition on the valve surface and subsequently resulting in vulnerability to infection. There is controversy regarding the relationship between mitral prolapse and embolic events.

Dilated cardiomyopathy

Mitral regurgitation is common in dilated nonischaemic cardiomyopathy. Dilatation of the left ventricle disturbs the normal closure of the mitral valve, the leaflets fail to coapt and hence mitral regurgitation occurs.

Pathophysiology and complications

Regurgitant orifice and jet

The regurgitant volume of mitral regurgitation is calculated as the regurgitant flow over the regurgitant area. The flow velocity through the orifice is related to the ventricular–atrial systolic pressure difference. A high left ventricular systolic pressure, e.g. systemic hypertension, increases mitral regurgitation volume, and low left ventricular pressure reduces it. Left atrial pressure in acute mitral regurgitation is raised, with a V-wave in late systole due to the increased volume and the velocity of blood entering it (although the absence of such a wave on the left atrial or pulmonary wedge pressure trace does not exclude the diagnosis of severe mitral regurgitation).

Mitral regurgitation is often a dynamic lesion, with the size of the regurgitant orifice and regurgitant volume varying with the pressure gradient across the valve and with changes in left ventricular volume and geometry. The use of medical therapy to reduce left ventricular volume and improve its systolic function may therefore assist in reducing the severity of mitral regurgitation.

Left atrium

Left atrial volume increases in patients with mitral regurgitation in response to the increase in its pressure, to the transmission of the mitral regurgitation kinetic energy to the left atrial wall, and also to the development (in some cases) of atrial fibrillation. These effects balance those of the mitral regurgitation jet on left atrial pressure, which is normal in compensated patients. In contrast to mitral stenosis, the fast regurgitant jet in the left atrium reduces the risk of thrombus formation.

Afterload

Mitral regurgitation is an isolated volume overload on the left ventricle, providing the physiological equivalent of afterload reduction so that a normal forward cardiac output is maintained by the combination of increased ejection fraction and higher preload. Therefore, unlike the situation with pressure overload, the coronary blood flow is normal and the increase in myocardial oxygen consumption in mitral regurgitation is only mild. Left ventricular dysfunction, manifest by increased end-systolic diameter, is one of the most important determinants of outcome.

Right heart

The risk of right heart disease and dysfunction in mitral regurgitation is very similar to that in mitral stenosis. The raised left atrial pressure and pulmonary venous pressure are directly reflected in right ventricular systolic pressure. Right ventricular dysfunction as a complication of pulmonary hypertension is an important determinant of outcome.

Clinical presentation

Symptoms

Patients with mild mitral regurgitation may not have any symptoms: those with severe regurgitation are likely to present with dyspnoea. It is sometimes reported that mitral valve prolapse may be associated with nonspecific symptoms such as chest pain and fatigue, but this is debatable.

Physical examination

The patient with nonrheumatic mitral regurgitation is usually in sinus rhythm, but with severe mitral regurgitation of any cause patients may present in atrial fibrillation. The pulse is likely to be of normal character, but is sometimes reported as ‘jerky’, meaning of normal amplitude but rapid upstroke. The venous pressure is normal unless there is significant pulmonary hypertension or associated tricuspid disease.

The apex beat may be prominent and displaced, may be double due to a palpable third heart sound, and there may be a palpable systolic thrill in severe cases. A palpable left parasternal heave may be due to systolic expansion of the left atrium and/or right ventricular hypertrophy.

The first heart sound is normal or soft, the most prominent findings on auscultation being an apical pansystolic murmur and a third heart sound. The loudness of the murmur generally correlates with severity of regurgitation, a murmur of less than grade 2/6 (meaning that it can be heard only with special effort) indicating mild disease, with the notable exception that no murmur may be audible with acute mitral regurgitation (when the mitral valve may effectively be absent). The cardinal signs of mitral prolapse are the mid-systolic click, due to the backward movement of the mitral leaflet into the left atrium, and the late systolic mitral regurgitation that occurs after the click. The murmur extends throughout systole as mitral regurgitation becomes severe.

The radiation of a mitral regurgitant murmur depends on the direction of the regurgitant jet. A posterolateral jet—seen in ischaemic mitral regurgitation, anterior leaflet disease and dilated cardiomyopathy—radiates from the apex to the axilla, and even to the back. An anterosuperior jet due to posterior leaflet prolapse is heard better at the lower left sternal edge or cardiac base (second right intercostal space, also known as the aortic area), and even on the carotids.

Other physical signs depend on the severity of mitral regurgitation and possible complications, e.g. pulmonary hypertension.

Investigations

Chest radiograph and electrocardiogram

The chest radiograph reflects the haemodynamic disturbance. The overall heart size is often normal or only moderately enlarged, with selective enlargement of the left atrium, although not to the same extent as with mitral stenosis. However, considerable cardiac enlargement develops due to secondary left ventricular disease if mitral regurgitation is severe and long standing.

The ECG usually shows sinus rhythm. There may also be evidence of left atrial hypertrophy, left ventricular hypertrophy and frequent ventricular ectopic beats.

Echocardiography

Two-dimensional echocardiography provides a thorough assessment of the anatomy and function of the mitral valve apparatus, including the leaflets and annular diameter, as well as left ventricular size and function, left atrial size, and pulmonary artery pressure. The echocardiographic criterion for mitral prolapse is the presence of at least 2 mm of late systolic posterior displacement of the leaflets across the mitral annular plane. Severe myxomatous degeneration is associated with thickening of the leaflets and the appearance of extensive folding or redundancy of the leaflets in diastole, chordal elongation, and systolic anterior motion of the leaflets. Secondary mitral prolapse can easily be distinguished from primary prolapse in patients such as those with Marfan’s syndrome, where the leaflets (particularly the anterior) are thin and long, and also in hypertrophic cardiomyopathy, with long leaflets and anterior motion of the mitral valve. Transthoracic echocardiography is perfectly adequate, but transoesophageal echocardiography is recommended if images are limited in quality.

Because it is noninvasive, echocardiography is an ideal tool for the follow up of patients to allow early identification of worsening of regurgitation or deterioration in ventricular function. Many echocardiographic methods for determining the severity of regurgitation have been described, three-dimensional reconstruction of the mitral regurgitation jet being a very promising tool for obtaining accurate regurgitant volume assessment since it avoids the conventional cross-sectional limitations. The extent of left ventricular cavity activity directly reflects the severity of volume overload, thus limiting the accuracy of using ejection fraction as a measure of ventricular function in such patients, hence changes in left ventricular end-systolic volume or dimensions should be taken as marker of ventricular dysfunction. Patients recommended for surgical repair need detailed transthoracic and transoesophageal echocardiographic assessment of the anatomy of the valve and subvalvular apparatus to assist surgeons in planning.

Findings that support pulmonary hypertension, in particular enlargement of the right side of the heart and increase in the retrograde pressure drop across the tricuspid valve, are easily obtained from a conventional Doppler echocardiographic study. Tricuspid leaflet prolapse is seen in 20% of patients with mitral valve prolapse, but aortic involvement is much less frequent.

Cardiac catheterization

This is not indicated for diagnostic purposes but may be required for preoperative assessment of the coronary arteries.

Differential diagnosis

Congenital VSDs are discussed in this article: Congenital heart disease in the adult, but the commonest scenario in adult practice where distinction between mitral regurgitation and VSD needs to be made is the patient who deteriorates shortly after a myocardial infarction and is found to have a pansystolic murmur. It is impossible to distinguish reliably between the two by physical examination, although if the murmur is heard over the back VSD is most likely. Echocardiography and/or right heart catheterization with measurement of oxygen tension in the various cardiac chambers are required.

The systolic murmur of aortic valve disease can radiate to the apex, and sometimes be louder there than at the base (aortic area). The latter can lead to misdiagnosis of mitral valve disease, and the former can lead to confusion as to whether both aortic and mitral valves are diseased. Aside from looking for other evidence of aortic valve disease (see later in this chapter), the key thing is to establish the precise timing of the murmur. Mitral valve disease should only be diagnosed if the murmur is pansystolic, extending right up to and even obliterating the second heart sound (or right up to the onset of the early diastolic murmur of aortic regurgitation).

The murmur of tricuspid regurgitation is typically loudest at the lower left sternal border, is loudest during inspiration, and is associated with elevation of the venous pressure with systolic waves.

Management

Patients with chronic mitral regurgitation may survive for a long time with no limiting symptoms. Once symptoms develop they suggest the need for surgical correction of valve regurgitation to avoid development of irreversible left ventricular dysfunction. Assessment during routine follow up identifies those likely to need surgical intervention even in the absence of symptoms, with an effective regurgitant orifice of over 40 mm2 being the cut-off recommended value. Although patients with acute regurgitation secondary to papillary muscle rupture need emergency surgery, this does not necessarily apply to those with ruptured chordae or chronic ischaemic regurgitation. Such patients need to be stabilized and other risk factors and comorbidities identified and optimally managed.

Medical

There is no medical therapy that cures mitral regurgitation or mitral valve prolapse. Endocarditis prophylaxis is recommended for high risk patients with regurgitation, although isolated mitral prolapse in the absence of regurgitation might not be counted as a definite indication. Symptomatic supraventricular arrhythmia needs optimum therapy, usually with β-blockers, and patients with ventricular tachycardia and syncope should be evaluated for implantable defibrillator (see: Cardiac arrythmias). Those in atrial fibrillation should be given anticoagulants and INR adjusted at 2.5 to 3.5.

Appropriate pacing for dilated cardiomyopathy has been reported as reducing the severity of mitral regurgitation. Vasodilators improve prognosis and also reduce preload and the venous return, which improves leaflet coaption and reduces mitral regurgitation. Their effect on the afterload improves the forward flow and also reduces the retrograde flow across the mitral valve. Carvedilol has been shown to reduce long axis length over diameter ratio (‘cardiac index’) and reduce mitral regurgitation severity. Similar findings have been documented in patients receiving ACE inhibitors or angiotensin receptor antagonists.

Surgical

A number of factors predict surgical outcome after correction of mitral regurgitation. As might be expected, the more complex the surgical procedure the higher the surgical risk. Age-related operative mortality is of the order of 12% in patients over 75 years of age and 1% in younger patients. Symptoms related to mitral regurgitation are important predictors: patients in New York Heart Association (NYHA) classes I and II carry a mortality of 0.5%, but for those in classes III and IV it is 10% or more. The aetiology of mitral regurgitation is another determinant, with 1 to 3% mortality in rheumatic mitral valve disease, compared to 9% in ischaemic mitral regurgitation.

Ventricular dysfunction adds to the surgical risk, in particular having an end-systolic dimension greater than 45 to 50 mm. However, recent data suggest that even significant left ventricular dysfunction should not be used as an exclusion criterion for correction of mitral regurgitation, although the general belief remains that a systolic dimension of more than 50 mm indicates a poor prognosis and that surgical intervention is unlikely to be of benefit. Pulmonary hypertension is another important predictor of outcome that carries a poor prognosis: correction of mitral regurgitation does not always guarantee normalization of pulmonary artery pressure, particularly if long-standing, which indicates that surgical intervention should be considered before development of this complication.

The intention of mitral valve repair is to preserve the integrity of the valve, which—if successful—results in a much better clinical outcome for patients with mitral regurgitation than does valve replacement. Preservation of the chordal attachment is crucial, keeping the continuity between the mitral leaflets and the papillary muscles which control the long axis function of the left ventricle. This itself also affects the sphericity of the left ventricle and hence overall performance of the cavity.

Mitral valve repair avoids the use of anticoagulants that are needed for life in patients with mechanical prostheses, and even those who develop atrial fibrillation from mitral valve repair might not need the higher dose of anticoagulants necessary for those who receive a mechanical valve. The risk of endocarditis is much lower from mitral valve repair compared to replacement.

As for any operation, patient selection for mitral valve repair is important. Although historical results of mitral valve repair for rheumatic regurgitation showed a success rate of 50%, better results have been reported recently, with a reoperation in approximately 20% of patients at 10 years. Surgical repair for rheumatic mitral valve disease is also affected by rheumatic aortic and tricuspid valve disease.

The most common procedure is the quadrilateral resection of the posterior leaflet, removing excess valve tissue, reapproximating the scallops, and reducing the annulus, with or without mitral annuloplasty. The success rate of this technique is of the order of 90%. Although historically anterior leaflet repair was not so easy as that of the posterior leaflet, recent advances have made it as successful. An alternative approach (not widely accepted in the surgical community) is the Alfieri repair, which involves suturing the posterior and anterior leaflets together in the central section and creating a double-orifice mitral valve.

It is now routine practice to use intraoperative transoesophageal echocardiography to provide detailed assessment and detect signs of valve dysfunction immediately on completion of surgery on the valve: residual regurgitation can be dealt with before closure of the chest.

In addition to mitral repair, patients with atrial fibrillation may be considered for arrhythmia ablation—surgically or by radiofrequency—to restore sinus rhythm. Results of the combined procedure have been satisfactory, even with chronic atrial fibrillation before surgery.

Mitral valve replacement

Mitral valve replacement has a higher operative mortality than aortic valve replacement for aortic stenosis or regurgitation, or conservative operation for mitral stenosis. Although survival from mitral valve replacement surgery has improved significantly over the years, probably because of the better selection, improved myocardial preservation, and surgical techniques, it remains of concern, particularly in patients with ischaemic mitral regurgitation, where 5-year survival is 75%.

The ideal valve would be a homograft in the mitral position, but this can only be achieved by use of a composite including the mitral valve and related structures and placing it attached to the annulus, which avoids cutting the papillary muscle heads and the chordae and preserves the continuity between the mitral valve apparatus and the left ventricle. However, such attempts have proved uniformly unsuccessful. Pulmonary autograft has been used in the mitral position with satisfactory results, but in only a small group of patients in one or two centres.

Mitral replacement by a mechanical valve or bioprosthesis is the only option for irreparable valves. It has a very satisfactory success rate, particularly when papillary muscles and chordae are preserved. Bileaflet or tilting disc are currently the most commonly used mechanical valves.

Mixed mitral valve disease

Mixed mitral disease is nearly always due to rheumatic valve disease. In general, it occurs in older patients than pure mitral stenosis, and the valve is more likely to be calcified with limited cusp mobility and scarred subvalve apparatus. The mitral regurgitation is not usually severe, but the increased stroke volume increases the diastolic pressure drop across the valve.

Symptoms are the same as for mitral stenosis or regurgitation. On examination the first heart sound is not palpable or loud, the pansystolic murmur is usually loudest towards the axilla, and there is a mid-diastolic murmur.

The chest radiograph may show more advanced changes than in pure mitral stenosis: the left atrium can be extremely large. Echocardiography is likely to show thickened cusps with reduced motion in addition to mitral regurgitation. When symptoms merit, valve replacement is usually required.

Aortic valve disease

Aortic stenosis

Causes

Aortic stenosis is caused by congenital, rheumatic or senile disease. It may be at subvalvar, valvar, or supravalvar level, the commonest being valvar stenosis.

Age-related degenerative calcific disease is now the commonest cause of aortic stenosis in western Europe and the United States of America. The commonest congenital valvar aortic disease is the bicuspid aortic valve, which may remain completely silent for years, but as age advances the leaflets become thickened and calcified resulting in significant reduction in valve area, raised transvalvar velocities and pressure drop (gradient) across the valve. Rheumatic aortic stenosis is nearly always associated with aortic regurgitation (mixed aortic valve disease, see below) and with rheumatic mitral disease. Symptomatic valvar aortic stenosis is more prevalent in men.

Subvalvar aortic stenosis is caused by a membrane (shelf) or a hypertrophied upper septal segment bulging into the outflow tract. Subaortic membrane is a congenital anomaly that commonly progresses with age. Hypertrophy of the upper septum is an acquired syndrome that affects the elderly, particularly those with long standing hypertension. Supravalvar aortic stenosis is rare: when found it is commonly part of Williams’ syndrome (OMIN 194050; ‘elfin’ facies with low nasal bridge, unusual behaviours and mental retardation, transient hypercalcaemia; supravalvar aortic stenosis).

Pathophysiology and complications

In addition to the anatomical narrowing of the aortic valve, left ventricular function plays an important role in determining the transvalvar velocities. Patients with severe aortic stenosis and poor left ventricular function may have underestimated velocities and pressure drop. By contrast, those with mild valve narrowing but a hyperactive ventricle (e.g. hyperdynamic circulation) may present with overestimated velocities across the valve; in particular, significant aortic regurgitation can lead to overestimation of the degree of valve stenosis because of increased stroke volume. Despite various attempts to determine the most sensitive marker of aortic stenosis, valve gradient (pressure drop) remains the most appropriate measure in clinical practice.

Left ventricular response

With the increase in outflow tract resistance in aortic stenosis, left ventricular wall stress increases and hypertrophy develops. This compensatory mechanism preserves overall ventricular systolic function. Most patients develop concentric left ventricular hypertrophy and increased mass, which regresses after removal of the stenosis. Patients with untreated aortic stenosis may present very late with left ventricular cavity dilatation, reduced ejection fraction and dyssynchrony. Left ventricular subendocardial ischaemia may result from long-standing ventricular hypertrophy and outflow tract obstruction, and diastolic left ventricular function also become impaired, resulting in increased end-diastolic pressure and left atrial pressure. Most patients with aortic stenosis who are allowed to reach this degree of ventricular dysfunction complain of progressive breathlessness and finally pulmonary oedema.

Coronary circulation

Even in the absence of significant coronary artery disease (atherosclerosis), the coronary circulation plays an important role in the pathophysiology and clinical presentation of aortic stenosis. Proximal coronary artery size is often increased, probably as a compensatory mechanism for the increased myocardial oxygen demand because of left ventricular hypertrophy, but coronary flow reserve remains suboptimal. This limited coronary flow reserve is manifested in the subendocardium, which may become irreversibly damaged, and the more severe the aortic stenosis, the greater the impairment of subendocardial function. Furthermore, left ventricular relaxation is usually prolonged in left ventricular hypertrophy, which further reduces coronary flow. The combination of hypertrophy-related altered coronary flow and increased myocardial work probably contributes to the angina-like symptoms, even in the absence of epicardial coronary disease. Regression of left ventricular hypertrophy after aortic valve replacement improves coronary flow reserve.

Clinical presentation

Symptoms

Mild aortic stenosis does not give any symptoms, and even severe stenosis may be silent. Breathlessness or exercise intolerance is the most common symptom. Progressive deterioration of left ventricular function and increased end-diastolic pressure leads to acute pulmonary oedema and florid heart failure. Angina is the second most frequent symptom, but less common than breathlessness. When it happens it represents a significant mismatch between myocardial oxygen supply and demand, and it may be exercise limiting even in the absence of epicardial coronary artery disease. The third symptom is syncope, which in some patients is clearly related to exertion. This can be caused by reduced cardiac output due to outflow tract obstruction, or by arrhythmia (transient atrioventricular block, ventricular arrhythmia, and carotid sinus hypersensitivity have all been described), with exercise-induced peripheral vasodilatation in the face of a fixed cardiac output the likely explanation for those who collapse when exercising.

Physical examination

The physical signs of significant aortic stenosis are very characteristic. Proper examination of the character of the pulse is crucial: a slowly rising, low-amplitude carotid (or brachial) pulse has high specificity for diagnosing severe aortic stenosis, and there may be a carotid thrill. Arterial pulse pressure is narrow.

The venous pressure is usually normal until late in the disease, but a small ‘a’ wave is often present. This is known as a Bernheim ‘a’ wave and appears to be related in some little-understood way to the presence of left ventricular hypertrophy and atrial cross-talk: it should not be taken in isolation as evidence of pulmonary hypertension.

The apex beat is often sustained and may be double, due to an additional left atrial impulse. On palpation of the praecordium there may be a systolic thrill over the aortic area in severe cases.

On auscultation the first heart sound is normal or soft, and may be preceded by a fourth heart sound. The characteristic long and harsh ejection systolic murmur is loudest at the base (second right intercostal space, also known as the aortic area) of the heart, and in most cases it radiates to the carotids. The murmur is often heard at the lower left sternal border, and in a minority the ejection systolic murmur may also be referred to the apex. A systolic ejection click may be heard, typically in patients with an uncalcified bicuspid valve. The second heart sound in aortic stenosis is typically single because of the limited cusp movement in a heavily calcified valve, but in young patients with severe aortic stenosis and mobile leaflets the splitting of the second sound is reversed. A normal split second heart sound is a reliable sign for mild aortic stenosis. A third heart sound may be heard when left ventricular cavity dilatation and raised left atrial pressure have developed. A soft early diastolic murmur is often present, which does not necessarily imply haemodynamically significant aortic regurgitation.

It is important to note these physical signs are modified as ventricular disease progresses and stroke volume falls. Pulse volume drops and the pulse loses its slow rising quality, the systolic murmur becomes shorter and softer and may even disappear, and a functional mitral regurgitant murmur can appear along with a third heart sound. Such ‘silent’ but critical aortic stenosis cannot be diagnosed reliably on the basis of physical signs: a high index of suspicion and a good quality echocardiogram are required to prevent misdiagnosis of ‘congestive cardiomyopathy, cause unknown’.

Investigations

Chest radiograph and electrocardiogram

The chest radiograph may be completely normal in patients with uncomplicated aortic stenosis. Post stenotic dilatation of the ascending aorta may be seen. Associated left ventricular disease leads to pulmonary venous congestion.

In most patients the ECG shows evidence of left ventricular hypertrophy based on voltage criteria, but in some cases it can be completely normal. Advanced hypertrophy may be associated with nonspecific T-wave changes. With progressive left ventricular dysfunction QRS duration broadens and left bundle branch block may develop. Inverted U wave may be seen in patients with severe left ventricular disease.

Echocardiography

Echocardiography is the investigation of choice for patients with aortic stenosis, providing comprehensive information on valve anatomy and function and left ventricular size and function, as well as other associated cardiac abnormalities that may contribute to patient’s symptoms, e.g. mitral valve regurgitation. Transthoracic echocardiography is mandatory in all patients with suspected aortic stenosis. Transoesophageal echocardiography may assist in examining the aortic root and the proximal ascending aorta.

The most clinically valuable measure of severity of aortic stenosis is transvalvular velocity using continuous wave Doppler. The blood flow sounds under two-dimensional echocardiographic guidance assist in deciding on the optimum positioning of the probe for velocity recordings, with the beam as parallel as possible to the jet direction. Peak velocities across the aortic valve are converted into a pressure drop (pressure gradient) using the modified Bernoulli equation, P = 4V2.

Timing of peak velocity across the valve is a good indicator of the degree of aortic stenosis: in mild stenosis velocities peak in early systole, but in severe stenosis velocities peak in mid systole, in parallel with the rise in aortic pressure.

Aortic stenosis can be quantified as valve area, which can be calculated from Doppler velocity data using the continuity equation based on the fact that the flow rate across the stenotic valve and the normal subvalvar area are equal. Valve area is therefore calculated based on the relative increase in blood velocity across the aortic valve with respect to the subvalvar region, in conjunction with an estimate of the subvalvar cross-sectional area. Thus, an increase in peak velocity across the aortic valve by five times that of subvalvar velocity, with a pressure gradient of at least 35 mmHg, is consistent with a fivefold drop in aortic valve area and suggests severe aortic stenosis.

An important application of this principle is seen in patients who have a moderate aortic pressure drop and in whom it is not clear whether this is simply because stenosis is not severe, or because stroke volume is low due to impaired left ventricular function. Stress echocardiography is a useful investigation in these circumstances. With increase in heart rate the increased blood flow across the valve differentiates between severe valve narrowing and severe left ventricular disease. A significant increase in transvalvular velocities and pressure gradient reflects fixed valve area and hence the diagnosis of severe aortic stenosis. By contrast, failure of aortic velocities to increase significantly with stress suggests impaired left ventricular function as the cause of the low cardiac output and symptoms rather than aortic stenosis.

Colour flow Doppler will reveal the presence of mild aortic regurgitation in most patients with aortic stenosis, and in those with impaired left ventricular function and raised end-diastolic pressure Doppler recordings of aortic regurgitation should be assessed carefully to avoid overestimating the degree of regurgitation because of raised left ventricular end-diastolic pressure.

Echocardiography can provide accurate measurements of left ventricular dimensions and systolic function, as well as left ventricular hypertrophy and mass, from which mass index can be calculated. Left ventricular filling pattern guides towards assessment of left atrial pressure. Most patients with aortic stenosis and left ventricular hypertrophy have a small early diastolic filling component and dominant late diastolic one. With progressive left ventricular disease and increase in end-diastolic pressure, the left atrial pressure increases and ventricular filling becomes of the restrictive pattern, with a dominant early diastolic filling component with short deceleration time and a very small late diastolic filling component with flow reversal in the pulmonary veins. Most patients presenting with this pattern of physiology have a dilated left atrium and some may even present with atrial arrhythmia. The extent of the commonly found mitral regurgitation can also be assessed, and other parameters enable estimation of the presence and degree of pulmonary hypertension. Mitral annular calcification is a very common finding in patients with severe aortic stenosis but rarely contributes to any increase in atrial pressure or results in mitral stenosis.

Cardiac catheterization

High-standard echocardiographic estimation of the severity of aortic stenosis is clinically very reliable and does not need to be reconfirmed by catheterization. The traditionally measured aortic pressure gradient during cardiac catheterization, using a pull-back technique to record the difference between peak left ventricular and aortic pressure, is a less satisfactory measure than that possible echocardiographically because the two peaks do not occur simultaneously. A further problem with estimation of aortic gradient by cardiac catheterization occurs because left ventricular pressure may not be uniform, hence the measured pressure difference depends on the location of catheter tip in the ventricle, particularly in the presence of significant hypertrophy as in most cases of aortic stenosis. The difficulty increases since aortic pressure also depends on its distance from the valve leaflets and the aortic wall, as well as the pressure recovery process in the aortic root. Such estimates should thus be regarded as semiquantitative.

Differential diagnosis

The commonest differential diagnosis that needs to be considered is aortic sclerosis, when examination of an elderly patient reveals an ejection systolic murmur at the base or left sternal edge. Other features of aortic stenosis—slow rising pulse, narrow pulse pressure, radiation of the murmur to the carotids, presence of a thrill—are not present.

All of these differential diagnoses can be distinguished from aortic stenosis by echocardiography.

Management

Progression of aortic stenosis is generally slow. Symptoms are variable but overall reflect left ventricular disease. Patients with a congenital bicuspid aortic valve tend to develop symptoms at an average age of 50 years, whereas those with senile valve disease do so at the age of 70 to 80 years. Patients with significant congenital aortic valve stenosis may develop symptoms earlier in life. Some 50% of patients with severe aortic stenosis die suddenly.

Raised aortic velocities and gradient, and the rate of increase in velocities over time, are the most accurate predictors of outcome, the rate of deterioration being faster in senile disease than rheumatic aortic stenosis. Once symptoms develop the outcome is poor without surgical intervention, with 5-year survival less than 50%. Autopsy series showed that the average time from symptom development to death is 2 years in patients with exertional syncope, 3 years in those with dyspnoea, and 5 years in those with angina. It should be highlighted that prognosis is much better in patients with a high valve gradient rather than those with low gradient due to severe left ventricular disease. Recent data suggests that patients presenting with an ejection fraction below 20% fail to thrive even after successful aortic valve replacement surgery.

Approximately 50% of adults with aortic stenosis who need surgery have additional coronary artery disease. Patients with angina-like symptoms who have only mild aortic stenosis are likely to have significant epicardial coronary disease, but a new onset of angina in patients with severe aortic stenosis may reflect a further deterioration of the degree of aortic stenosis and subendocardial ischaemia. A particularly difficult group of patients to manage are those with moderate aortic stenosis and angina-like symptoms.

Medical

There is no medical treatment for aortic stenosis that will stop disease progression. Asymptomatic patients with mild or moderate aortic stenosis require follow-up; those with severe aortic stenosis need aortic valve replacement. It is prudent to advise those with moderate or severe disease to avoid strenuous exercise. A pressure gradient of more than 70mmHg across the aortic valve is a good indication for surgery, particularly in those who are symptomatic. Patients with severe aortic stenosis and left ventricular disease who present with heart failure should be stabilized before referral for surgery: diuretics are important, as well as β-blockers for controlling the heart rate; vasodilators, including ACE inhibitors, are contraindictated. Once a patient develops raised left atrial pressure and pulmonary hypertension the outcome is less than satisfactory, even with surgery.

Instructions on endocarditis prophylaxis and the use of antibiotics before dental and surgical procedures should be given to high risk patients. Patients with other comorbidities and risks, in particular hyperlipidaemia, should have these addressed. The effect of statins on the rate of progression of aortic stenosis seems to be negligible.

Surgical

Recent advances in aortic valve surgery—earlier intervention, changes in the procedures used, improved methods of myocardial preservation—have resulted in a significant fall in surgical mortality to 2.7 to 8.3% in adults under 70 years of age. Concurrent coronary artery disease, ventricular dysfunction, and pulmonary hypertension are important surgical risks. Older patients with aortic stenosis, particularly those over the age of 80 years, tend to have a higher mortality, but age is not a contraindication to surgery. Surgical intervention in octogenarians has been shown to provide improvement in quality of life, with a 5-year postoperative survival compared to only 1 year for the unoperated.

Aortic valve repair

In young people aortic valvotomy is an acceptable procedure, but the option of valve repair in adults remains uncertain. It may provide a medium-term solution for a clinical problem, but further surgical intervention will definitely be required in the long term.

Tissue valves

Tissue valves do not need anticoagulants in the absence of atrial fibrillation. Although their durability is significantly lower than that of mechanical valves, indications for their use are clear: older people, young pregnant women, and patients with limited access to anticoagulant therapy. Over the years the durability of tissue valves has significantly improved: for patients over the age of 60, modern, third-generation, glutaraldehyde-preserved valves provide 90% survival at 15 years. Stentless tissue valves have better durability and are associated with faster recovery of ventricular function, but they are more difficult to implant.

The best option to replace a native valve is a human valve (homograft), but availability is limited. An aortic valve homograft replacement is particularly indicated in patients with endocarditis that involves the aortic root and is associated with abscess formation, because a mechanical valve replacement in this scenario compromises eradication of the infection. Aortic homograft implantation techniques have evolved from a two-layer subcoronary implantation to conduit implantation, which involves replacing the valve and sinus of Valsalva by a full root and valve. This still is considered more challenging than mechanical or tissue valve implantation. Under the age of 30 years aortic homografts tend to fail within 10 years: in older patients the mean survival of the valve is 15 to 18 years.

An alternative procedure is the pulmonary autograft or ‘Ross procedure’. This goes back to 1967 when Donald Ross transferred a patient’s own living pulmonary valve to the aortic position and inserted a homograft in the pulmonary position. In children these autograft valves, unlike any other valve substitute, are capable of growth. A pulmonary homograft is placed in the right ventricular outflow tract, where because of the lower pressures on the right side of the circulation the mean survival of the valve is 20 years. More recently, percutaneous replacement of the aortic (TAVI procedure) valve has become an alternative for high surgical risk patients with worldwide satisfactory result.

Mechanical valves

Over the years technical improvement in valve design has been remarkable, providing larger orifice area and greater resistance to thrombosis. In the long term the commonest problem, affecting less than 5% of patients with mechanical prostheses, is paravalvular dehiscence. While this may not always be haemodynamically significant, it may be responsible for haemolytic anaemia due to shear stress on red blood cells, and it is a focus for infective endocarditis. Valve dysfunction due to subvalvar tissue ingrowth that influences valve opening and closure remains a problem.

Pathophysiology and complications

The left ventricular stroke volume, which equals the forward stroke volume plus the regurgitant volume, is significantly increased in aortic regurgitation. This is accommodated by an increase in left ventricular cavity size, a process that is progressive in a similar fashion to that of mitral regurgitation, although the degree of ventricular dilatation is greater. Another difference between the two conditions is the peripheral vascular resistance, which is significantly raised only in patients with aortic regurgitation. This combination of volume overload and raised peripheral resistance results in a progressive increase in left ventricular wall thickness and mass. In uncomplicated aortic regurgitation, the left ventricular ejection fraction is maintained, but as the disease progresses end-systolic volume increases out of proportion to stroke volume, and eventually these changes lead to irreversible damage which persists even after surgical correction of the aortic regurgitation.

Whether or not aortic regurgitation is accompanied by some degree of aortic stenosis due to intrinsic valve leaflet disease, the increase in stroke volume causes high systolic velocities across the aortic valve. Pressure relations between the aorta and the left ventricle in diastole are of great importance, in particular the end-diastolic pressure difference that depends not only on aortic but also on left ventricular end-diastolic pressure: the higher the left ventricular end-diastolic pressure the lower the pressure difference across the valve. In mild aortic regurgitation the pressure drop between the aorta and the left ventricle is maintained throughout diastole. By contrast, with acute aortic regurgitation the pressure difference between the aorta and the left ventricle falls to 15 mmHg or even less before end of diastole, either because of the very low resistance at the valve level or because the left ventricle is stiff, hence a relatively small regurgitant volume causes a disproportionate left ventricular diastolic pressure rise. This disturbed physiology has major implications because the aortic–left ventricular diastolic pressure gradient is the pressure head supporting the coronary flow. Coronary autoregulation stops at a perfusion pressure difference between the aorta and the left ventricle of 40 mmHg, and with acute aortic regurgitation—or even severe chronic aortic regurgitation—the gradient is less than this, resulting in significant myocardial ischaemia and progressive ventricular dysfunction. This disturbed physiology may be tolerated in chronic severe aortic regurgitation, but in acute severe aortic regurgitation it may contribute to rapid clinical deterioration. The limitation of coronary flow by a raised ventricular end-diastolic pressure is further exacerbated by the increased oxygen demand of the myocardium as a result of the hyperdynamic ventricular state, as well as (in chronic regurgitation) the hypertrophy resulting from the volume overload. This results in subendocardial ischaemia, particularly with stress.

Clinical presentation

Symptoms

Patients with aortic regurgitation may remain asymptomatic for a long time. The onset of symptoms, particularly breathlessness, coincides with the onset of left ventricular disease, a significant rise in end-diastolic pressure, and development of pulmonary venous hypertension. Angina is an uncommon symptom in chronic aortic regurgitation, but when it occurs it should suggest significant subendocardial ischaemia as a result of the mismatch between the coronary artery flow and myocardial mass. It is more common in those with acute aortic regurgitation. Any sudden worsening of symptoms may reflect acute deterioration of the degree of aortic regurgitation or impairment of left ventricular function.

Physical examination

The physical signs of significant chronic aortic regurgitation are characteristic. The pulse has large amplitude and is ‘collapsing’ in nature (‘water hammer’, Corrigan’s pulse) due to the increased stroke volume and rapid fall-off in aortic pressure during diastole. When severe, this can induce pulsations in many parts of the body, generating many eponyms that describe what is effectively a single physical finding. Amongst the better known of these are Quincke’s capillary pulsations (best demonstrated by blanching a portion of a fingernail by applying gentle pressure and observing the pulsating border between the white and the red segments), de Musset’s sign (bobbing of the head in time with the arterial pulse, named after the French poet who had the condition), and pulsations of various organs or their parts (uvula—Muller’s sign, retinal arteries—Becker’s sign).

The same pathophysiology underlies two peripheral arterial signs. Pistol shot sounds are short, loud sounds that can be heard over large peripheral arteries if the stethoscope is lightly applied: they occur because of sudden expansion and tensing of the walls during systole. Duroziez’s sign is a double to-and-fro (systolic and diastolic) murmur heard over the brachial or femoral artery if the stethoscope is firmly applied: the diastolic component results from reversal of flow in the artery during diastole.

A diastolic blood pressure of less than 50 mmHg and/or a pulse pressure of 80 mmHg or more suggest moderate or severe regurgitation in patients who have a characteristic murmur (but are of no significance with regard to the aortic valve if no murmur is present). The venous pressure is normal until late in the course of disease, although a dominant Bernheim ‘a’ wave may be seen. The apex beat is sustained and/or displaced because of the left ventricular hypertrophy and/or dilatation.

On auscultation the classical murmur of aortic regurgitation is diastolic, starting immediately after the second heart sound, decrescendo in nature, and loudest at the left sternal border. It may be short, or extend throughout diastole. It may radiate to the right sternal border if it is caused by aortic root dilatation, and rarely it is loudest at the apex or even in the left axilla. The louder the murmur, the more severe is the regurgitation. The heart sounds may not demonstrate any specific change in aortic regurgitation, or—as with aortic stenosis—the aortic component of the second heart sound may be absent. An ejection systolic murmur due to increased stroke volume is nearly always present. At the apex a low-pitched mid-diastolic murmur (Austin–Flint murmur) mimicking that of mitral stenosis may be heard: it is usually assumed that this is due to the aortic regurgitant jet striking the anterior leaflet of the mitral valve, but other hypotheses have been advanced.

In acute aortic regurgitation—usually caused by infective endocarditis, thoracic aortic dissection, or disintegration of a tissue valve replacement—the physical signs are quite different, based on the fact that the stroke volume in acute regurgitation does not increase by the same magnitude as in chronic regurgitation. The patient is cold and shut down due to a low cardiac output, with tachycardia, a low systolic blood pressure and low pulse pressure, and a short early diastolic murmur that is easily missed. The apex is not displaced and peripheral signs are absent. There may be a loud third heart sound.

Investigations

Chest radiograph and electrocardiogram

The chest radiograph may show increased cardiothoracic ratio and dilatation of the aortic root. In isolation these appearances cannot be taken as diagnostic, but they are very useful for follow-up of a known case.

The 12-lead ECG may demonstrate increased voltage and a ‘strain’ pattern that correlates with increase in left ventricular cavity dimensions, hypertrophy, and wall stress. The voltage pattern may fall significantly after correction of the aortic regurgitation and regression of left ventricular mass. Nonspecific T-wave changes may occur with exercise, reflecting either the development of subendocardial ischaemia or increase in systolic left ventricular volume. Increased QRS duration is a marker of left ventricular disease. A long PR interval may indicate aortic root abscess, particularly in those with other clinical suspicion of endocarditis.

Echocardiography

Doppler echocardiography is an invaluable investigation in the assessment of patients with aortic regurgitation. Two-dimensional images can identify the exact cause of regurgitation, revealing the valve anatomy, leaflet number, calcification, or evidence of infection. The diameter of the aortic root and proximal ascending aorta can also be measured. Transoesophageal examination is always recommended if this is not achievable on transthoracic images, particularly in patients with Marfan’s syndrome or those presenting with suspected dissection. Left ventricular size, dimensions, wall thickness and ejection fraction can easily be measured, and muscle mass calculated using simple formulae. Colour Doppler detects the presence of aortic regurgitation and gives some idea of its severity: the finding of large vena contracta, a large regurgitant orifice area, penetration of the regurgitant jet into the left ventricle, and jet diameter more than 50% of the aortic root diameter are all consistent with significant regurgitation. Continuous wave Doppler is ideal for assessing regurgitation severity as well as pressure differences between the aorta and the left ventricle: in general, the faster the pressure decline on the aortic regurgitation trace, the more severe is the regurgitation likely to be, although this does not apply in patients with raised end-diastolic pressure. Doppler can also confirm severity of aortic regurgitation by demonstrating flow reversal in the descending aorta or femoral arteries. In patients with symptoms disproportionate to the degree of aortic regurgitation, a diagnosis of left ventricular disease should be considered, e.g. hypertension or coronary heart disease.

In acute aortic regurgitation echocardiography demonstrates clearly the cause of the disease; endocarditis with its complications or disintegrating homograft or bioprosthesis. M-mode echocardiography shows premature mitral valve closure which, together with the left ventricular activity, support the diagnosis of acute aortic regurgitation.

Cardiac catheterization

Cardiac catheterization is not needed to assess the severity of aortic regurgitation: it is only needed to confirm the presence of additional coronary artery disease, particularly before surgical intervention.

Differential diagnosis

It can sometimes be difficult to distinguish the early diastolic murmur of aortic regurgitation from that caused by pulmonary regurgitation (Graham–Steell murmur). In this circumstance no other features of aortic regurgitation are expected, and pulmonary regurgitation is usually associated with other signs indicating the presence of significant pulmonary hypertension (including a large pulmonary artery on the chest radiograph).

Other causes of aortic run-off, including persistent ductus arteriosus, ruptured sinus of Valsalva aneurysm, and coronary arteriovenous fistula, can also produce auscultatory findings that can be confused with aortic incompetence. However, they all cause a continuous murmur, rather than one confined to diastole.

Management

It is uncommon for mild aortic regurgitation to progress rapidly to severe regurgitation, hence the importance of Doppler echocardiography in the follow-up of patients. Identification of the cause of aortic regurgitation helps in determining how often patients should be reviewed: those with mild aortic regurgitation due to aortic root or ascending aorta disease should be followed up more closely than those with stable valve disease. Patients with moderate or severe aortic regurgitation may have no symptoms for years. As symptoms always reflect ventricular dysfunction, a progressive increase in end-systolic dimension/volume should be taken as an indication for serious consideration of surgery, even in the absence of symptoms. Ejection fraction cannot be taken as a marker of ventricular function in aortic regurgitation because of the volume overload and overestimation of the ejection performance: an end-systolic dimension up to 40 mm carries a good prognosis, whereas a dimension more than 50 mm is associated with 20% possibility of developing ventricular dysfunction, symptoms, or even death over a course of 5 years.

In the same way that patients with aortic regurgitation secondary to aortic valve disease are managed, those with aortic regurgitation associated with or causing aortic root dilatation should be followed up to assess the aortic root dimensions, with the aim of preventing progressive dilatation and the potential risk thereof. Some patients with a bicuspid aortic valve develop progressive dilatation of the aortic root because of the eccentric jet, as well as the accompanying aortopathy. Another group of patients who need regular follow-up and careful aortic root assessment are those with Marfan’s syndrome, in whom aortic root aneurysmal dilatation and dissection are the major causes of morbidity and mortality. In addition to using conventional Doppler echocardiography, CT scanning and MRI can play a useful role in the follow-up of patients with aortic root or ascending aorta disease, and three-dimensional echocardiography for assessment of left ventricular size and function (see articles: Echocardiography and Cardiac investigation—nuclear and other imaging techniques for further discussion).

Medical

Medical management in aortic regurgitation aims at slowing down its progression, supporting the left ventricle, and determining the optimal time of surgical intervention. The increased afterload in patients with aortic regurgitation should be managed medically to reduce the wall stress and the diastolic driving pressure across the valve. Doing so decreases the pressure and the volume overload on the left ventricle and prevents progressive left ventricular dilatation and systolic dysfunction, and can delay the need for surgery. This effect has been demonstrated using ACE inhibitors and calcium channel blockers, the choice of the pharmacological agent for left ventricular afterload reduction depending on the other comorbidities, e.g. coronary artery disease, as well as patient tolerance.

Patients with aortic root dilatation should not be treated with vasodilators alone. In this instance β-blockers are recommended because they decrease aortic wall stress, blood pressure, and the rate of pressure increase in systole. Although patients with Marfan’s may remain completely asymptomatic, the rate of aortic root dilatation is the most important risk factor. It may be that the combination of β-blockade with ACE inhibition/angiotensin receptor blockers (possibly acting through inhibition of TGF-β signalling) may prove effective in retarding or even preventing dilatation. However, when dilatation does occur previous guidelines have suggested that aortic root dimension larger than 55 mm is a good indication for surgical intervention, although recent recommendations have advocated an earlier surgical approach, particularly in the presence of family history of dissection. See: Cardiac involvement in genetic disease for further discussion.

As is the case with all valve disease, oral hygiene should be encouraged in patients with aortic regurgitation and prophylactic antibiotics prescribed to cover dental, proctological, urological, and gynaecological surgeries for patients at risk.

Surgical

Although patients with severe chronic aortic regurgitation may remain asymptomatic, surgical intervention should be offered when there is progressive increase in systolic dimension. A left ventricular end-systolic dimension of 40 mm is a cut-off value for preserved left ventricular systolic function, particularly for an active ventricle. Predictors of outcome after valve surgery are severe aortic regurgitation, age, severe symptoms, exercise intolerance, and evidence for left ventricular hypertrophy on echocardiography. Raised left ventricular end-diastolic pressure and the ratio of wall thickness to chamber dimension have also been identified as potential predictors of outcome. An additional risk is the presence of coronary artery disease. These patients should be carefully evaluated by preoperative cardiac catheterization and receive myocardial revascularization surgery and coronary grafting at the same setting with aortic valve replacement surgery. There is evidence to suggest that patients with aortic regurgitation and ventricular dysfunction develop faster reverse remodelling and fall of left ventricular mass index following successful valve replacement if they receive a stentless rather than a stented valve. Details of surgical procedures for aortic regurgitation are as described in the preceding section on aortic stenosis.

Acute aortic regurgitation, irrespective of its aetiology, should be managed as an emergency with surgical intervention. While diagnostic evaluation is in progress the patient should be treated with afterload reduction. Aortic balloon counter pulsation is contraindicated because it increases afterload. Cases caused by infective endocarditis should receive optimal antibiotic therapy following blood culture and emergency valve replacement, which could be life saving.

Mixed aortic disease

Mild to moderate aortic regurgitation often accompanies aortic stenosis but does little to alter the overall clinical picture. The combination can result from a bicuspid aortic valve or chronic rheumatic heart disease, or be the result of endocarditis or conservative surgery on a stenosed valve. The main haemodynamic disturbance is increased resistance to ejection, but the superimposition of even a moderately increased stroke volume due to regurgitation on the small, stiff left ventricle of pure aortic stenosis can lead to high filling pressures, left atrial enlargement, and even pulmonary hypertension. Breathlessness and chest pain are the most prominent symptoms. The arterial pulse is bisferiens, and typical ejection systolic and early diastolic murmurs are expected. Patients with symptoms are likely to require valve replacement.

Right heart valve disease

Many of the conditions that affect right sided valves are congenital: these are discussed in detail in: Congenital heart disease in the adult. Particular pulmonary and tricuspid valve diseases that develop later in life are discussed here, after general discussion of effects of abnormal right-sided haemodynamics on right heart function and diagnostic techniques.

Pathophysiology and complications

Right ventricular response to valve disease

The right ventricle responds to chronic pressure overload, e.g. caused by pulmonary stenosis or pulmonary hypertension, by hypertrophy and early dilatation. With increased afterload and right ventricular dilatation the ventricle adapts by making the intraventricular septum function as part of the right heart. This can be identified by studying septal movement during various phases of the cardiac cycle using M-mode echocardiography, revealing that it becomes reversed in systole and in diastole. Right ventricle dilatation includes the tricuspid annulus and results in tricuspid regurgitation. Eventually right ventricular systolic function deteriorates, which may become irreversible even after correcting the volume or pressure overload. With right ventricular volume overload the ventricle is very active, readily apparent on recording its free wall movement at the level of the tricuspid ring. However, assessing right ventricular ejection fraction and overall systolic function is difficult because of its complex anatomy, being made of an inlet portion and an outlet portion that are at a significant angle to each other, and a trabecular portion at the apex.

Assessment of right ventricular size and function

A three-dimensional approach to the assessment of right ventricular systolic function is the ideal method, but other cross-sectional echocardiographic and MRI techniques have developed over the years and proved sensitive in assessing right ventricular ejection fraction. Right ventricular inlet diameter can be used as a marker of cavity dilatation. Free wall long axis movement studied by M-mode and tissue Doppler imaging from the lateral angle of the tricuspid annulus is an easy measure of systolic function and correlates closely with right ventricular ejection fraction. Likewise, right ventricular outflow tract diameter has been shown a sensitive measure of systolic function. In patients with reversed septal movement it is crucial to exclude any shunt as a cause for volume overload in the right ventricle.

Estimation of pulmonary artery pressure is an essential component in the evaluation of patients with right-sided valve disease. The retrograde flow velocity across the tricuspid valve gives an indication of systolic right ventricular pressure by use of the simplified Bernoulli equation. In all patients systolic pulmonary artery pressure equals the retrograde peak pressure drop across the tricuspid valve added to the estimated right atrial pressure, according to the collapsibility of the inferior vena cava. These measurements are clinically useful in patients without pulmonary stenosis.

Investigation of valve stenosis and regurgitation

The methods used in clinical practice for investigating possible tricuspid and pulmonary valve stenosis and regurgitation are the same as those used in assessment of conditions affecting the left side of the heart. Colour Doppler detects the level at which there are increased velocities as a sign of valve narrowing, which can be confirmed by continuous wave Doppler. In patients with valve regurgitation colour Doppler assesses the jet diameter, direction, and area which, with respect to the right atrial area in cases of tricuspid regurgitation, gives some indication of the severity of tricuspid regurgitation. Transoesophageal echo images, particularly in tricuspid valve disease, provide detailed assessment of valve pathology.

Transthoracic images of the pulmonary valve can be somewhat limited technically, but in most cases Doppler studies can exclude significant valve disease based on forward and backward velocities and pressure drop. Transoesophageal echo provides a clearer image of the pulmonary valve and so is best suited for determining the level of valve stenosis. The degree of pulmonary stenosis and regurgitation severity is assessed by continuous wave Doppler, with timing of reversal of regurgitant pulmonary flow another confirmation of its severity. Mild pulmonary regurgitation occupies the whole of diastole, while in severe regurgitation there is early pressure equalization between the two chambers. A jet diameter of 7 mm or more also supports the diagnosis of severe pulmonary regurgitation.

MRI is another good noninvasive technique for assessment of right-sided chamber size and valve function, in particular the pulmonary valve. The level of narrowing can easily be determined, the degree of stenosis by velocity mapping, and severity of regurgitation by estimating the regurgitant volume.

Tricuspid stenosis

Tricuspid stenosis is a rare condition, most often caused by rheumatic disease, which almost invariably simultaneously affects the mitral valve. Other (even rarer) causes are carcinoid disease, infective endocarditis, and Whipple’s disease. A right atrial myxoma or extension of hypernephroma into the inferior vena cava and right atrium can in very rare instances present with signs and symptoms of right ventricular inflow tract obstruction, similar to tricuspid stenosis.

Symptoms include fatigue, dyspnoea, and fluid retention. In patients with chronic rheumatic heart disease the problem is to recognize that the tricuspid valve has been affected in addition to the mitral (and perhaps the aortic valve as well). If the patient is in sinus rhythm there may be an ‘a’ wave in the venous pulse, which would be unusual in the presence of pulmonary hypertension and mitral stenosis alone (when the patient is very likely to be in atrial fibrillation). On auscultation at the left or right sternal edge a mid-diastolic murmur (usually higher in pitch than the murmur of mitral stenosis) is heard, and a tricuspid opening snap may be present (later in the cardiac cycle than a mitral opening snap, and varying in timing in relation to P2 with respiration), although it is not possible to differentiate this reliably from the mitral opening snap that is likely to coexist.

The chest radiograph shows a large right atrium with normal pulmonary artery size and clear lung fields. Echocardiography shows a dilated right atrium and demonstrates clearly the valve anatomy and function, as well as other intracardiac pathologies. The echocardiographic signs of rheumatic tricuspid disease are similar to those of the mitral valve, including commissural fusion, fibrosed leaflets that dome in diastole, short and fibrosed chordae, and raised transtricuspid forward flow velocities.

Tricuspid valve disease progresses very slowly and needs careful follow-up. Medical treatments are not satisfactory: diuretics can help to minimize fluid retention, but at the expense of reduced cardiac output if pushed too hard. Mild and moderate tricuspid stenosis is generally tolerated; severe tricuspid stenosis needs surgical repair, or replacement if additional regurgitation is present.

Tricuspid regurgitation

Mild tricuspid regurgitation is found in 50% of normal individuals. Causes of significant tricuspid regurgitation are shown in Table 3, the commonest being secondary to either pulmonary hypertension or right heart dilatation.

Table 3 Causes of tricuspid regurgitation

Cause

Type of condition

Disease

Primary

Congenital

Ebstein’s anomaly

Atrioventricular defect

Prolapsing cusp

Acquired

Rheumatic fever

Infective endocarditis

Permanent pacemaker wires

Endomyocardial fibrosis

Blunt trauma to the chest

Carcinoid syndrome

Ergot-derived dopamine receptor agonists

Following radiotherapy to the chest

Secondary

‘Functional’

Pulmonary hypertension or right heart dilatation

Ischaemic right ventricular disease

Endocarditis is commonly caused by intravenous access, either in those who abuse drugs intravenously, or in patients who required prolonged right-heart catheters for medical therapy. Endomyocardial fibrosis, which is prevalent in tropical Africa, causes fibrosis of the papillary muscle tips and thickening and shortening of tricuspid valve leaflets and chordae. Permanent pacemaker wires across the tricuspid valve may rarely cause leaflet adhesions and dysfunction. Blunt trauma to the chest may be complicated by tricuspid regurgitation through the papillary muscle or chordal lacerations. Metastatic carcinoid tricuspid valve disease is rare, but echocardiographic findings of carcinoid involvement of the tricuspid valve are very characteristic, showing short, fibrosed, and thickened leaflets resulting in larger areas of incomplete coaption and severe tricuspid regurgitation. Tricuspid valve prolapse is occasionally seen in patients with mitral valve prolapse.

The symptoms of tricuspid regurgitation are usually nonspecific. When it develops in a patient with mitral stenosis it is often associated with increased fatigue rather than breathlessness. Some patients will present with increasing peripheral oedema, and hepatic congestion may cause nausea or upper abdominal pain exacerbated by exercise. Diarrhoea caused by a protein-losing enteropathy (thought to be secondary to venous congestion of the gut) has been reported.

The main physical sign is a raised venous pressure with prominent V-wave, without which the diagnosis of significant tricuspid regurgitation is very difficult to sustain. In about one-third of cases a pansystolic tricuspid regurgitation murmur can be heard at the left or right sternal edge: this tends to increase in intensity with inspiration as the venous return increases, and it can radiate into the epigastrium. Expansile pulsation of the liver is present in most cases, but hepatic fibrosis (and jaundice) can occur if regurgitation is long-standing and this physical sign then disappears. Most patients with severe regurgitation have peripheral oedema, ascites, or both.

The findings on a chest radiograph depend mainly on whether or not the patient has any other cardiac disease, but there may be enlargement of the heart shadow towards the right. The ECG may show right atrial hypertrophy. Echocardiography is the best way to make the diagnosis. Cardiac catheterization is not required for assessment of tricuspid regurgitation but may be indicated for diagnosis or assessment of other concurrent heart disease.

Many patients tolerate tricuspid regurgitation for a long time, but some present with symptoms that significantly limit their exercise capacity and lifestyle. Medical treatment with diuretics and ACE inhibitors may reduce systemic venous pressure and right ventricular size, even restoring competence to the tricuspid valve in some cases. Attempts should be made to treat pulmonary hypertension if this is the primary cause of right ventricular dilatation and tricuspid regurgitation. If fluid retention is severe and refractory to medical treatment, careful consideration should be given to surgical correction of tricuspid regurgitation before the patient develops irreversible right ventricular damage. Repair and replacement of the tricuspid valve are problematic operations, with the former sometimes failing to prevent regurgitation and the latter leading to a significant diastolic pressure drop between the right atrium and ventricle, creating a problem of iatrogenic tricuspid stenosis, but in specialist centres the current approach is less conservative than it used to be.

Tricuspid valvuloplasty is often performed at the time of mitral valve surgery for rheumatic disease. Annuloplasty involves a full ring, incomplete ring, or suture plication of the annulus. A semicircular ring has the advantage of maintaining annular flexibility and avoiding conduction disturbances, but residual tricuspid regurgitation occurs less often with a circular angioplasty ring than with a semicircular one. Tricuspid valve replacement by a mechanical prosthesis has a potential risk for endocarditis, particularly in drug abusers. Bioprostheses have a much lower thrombogenicity and resistance to flow in the tricuspid position and are therefore the preferred choice.

The surgical mortality of tricuspid valve surgery depends particularly on the degree of preoperative hepatic congestion. Survival following tricuspid valve replacement is not purely related to the surgical procedure itself or to valve function, but is significantly affected by right ventricular dysfunction that is almost always masked by the volume overload before surgery.

Pulmonary stenosis

Pulmonary stenosis is congenital in 95% of cases (see: Congenital heart disease in the adult): rarely it is caused by rheumatic valve disease or carcinoid syndrome. Patients can tolerate moderate pulmonary stenosis (gradient <50 mmHg) for years, fatigue and dyspnoea due to reduced cardiac output being the main symptoms in those with severe disease. Physical examination reveals a prominent venous ‘a’ wave in the neck and an ejection systolic murmur at the upper left sternal edge that radiates to the suprasternal notch and left side of the neck. With severe pulmonary stenosis the pulmonary component of the second sound may be delayed, but it is often inaudible. An ejection click may be heard at the upper left sternal edge. Echocardiography and MRI show the level of stenosis. Doming leaflets are consistent with congenital valve disease. MRI imaging is particularly good for demonstrating supravalvar stenosis. Event-free survival is related to the pressure gradient across the pulmonary valve.

Balloon valvuloplasty is the procedure of choice for children and adults with significant pulmonary stenosis. On average transpulmonary gradient drops by two-thirds of the baseline value without development of significant pulmonary regurgitation. Additional subvalvar stenosis may underestimate the success of the procedure. Surgical valvotomy may be considered if balloon valvuloplasty fails, and valve replacement may be needed for those with iatrogenic significant pulmonary regurgitation, especially after repair of tetralogy of Fallot. Homograft replacements might be advantageous to avoid anticoagulation and thrombogenicity.

Pulmonary regurgitation

A small amount of pulmonary regurgitation is common. Significant pulmonary regurgitation is very rare and most commonly preceded by intervention to the pulmonary valve during childhood. Although the outcome of repair of tetralogy of Fallot is excellent in most cases, many of its complications are related to pulmonary regurgitation. Rare causes of pulmonary regurgitation are rheumatic disease, carcinoid, and endocarditis. Many patients with pulmonary hypertension and dilatation of the right ventricular outflow tract will demonstrate some degree of pulmonary regurgitation.

The typical murmur of pulmonary regurgitation is a soft early diastolic murmur that is best heard in the left upper parasternal region. It begins after the pulmonary component of the second sound and may be accompanied by an ejection systolic murmur caused by increased stroke volume. Most patients have enlarged neck veins and other evidence of pulmonary hypertension.

Most patients with mild pulmonary regurgitation remain completely asymptomatic for years. Although those with severe regurgitation may remain asymptomatic, correction of valve incompetence may save them irreversible damage of the right ventricle. Arrhythmia or progressive right ventricular dilatation are indications for surgery, using homograft or conduit and valve. Normalization of right ventricular size and function following pulmonary homograft insertion occurs in some but not all patients, probably depending on preoperative ventricular dysfunction that could be masked by volume overload.

Mitral valve disease

Bonow RO, et al. (2006). ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol, 48, e1–148.

Bonow RO, et al.(2008). American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 52, e1–142. [2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.

Vahanian A, et al.(2008). Eur J Cardiothorac Surg, 34, 1–8.[ Transcatheter valve implantation for patients with aortic stenosis: a position statement from the European Association of Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI).

Endocarditis

Habib G, Hoen B, Tornos P, et al.; ESC Committee for Practice Guidelines (2009). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J, 6, 475–81.

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